Duration of treatment also intensifies relationship with unusual bone breaks.

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MONDAY, May 21, 2012
(MedPage Today) —Bisphosphonate
therapy appears to be associated with an increased risk of atypical
fractures of the femur, and may be driven by the duration of treatment,
according to new research.

Of 477 patients hospitalized at one
center, 39 had atypical fractures and 438 had common fractures. Among those
with atypical fractures, 82.1 percent had been taking bisphosphonates compared
with just 6.4 percent of those with common fractures, Raphael P.H. Meier, MD,
from University Hospitals of Geneva, and colleagues reported online in the Archives
of Internal Medicine.

They also noted that the atypical-fracture
group had a longer treatment period on bisphosphonates — including
alendronate (Fosamax), risedronate (Actonel), pamidronate (Aredia), and
ibandronate (Boniva) — than the classic-fracture group, at a mean of 5.1 years versus 3.3 years.

Nonetheless, compared with a 200-patient
fracture-free control group, use of bisphosphonates was associated with a 47
percent reduction in the risk of common fractures, making the absolute
risk:benefit ratio of bisphosphonates a positive one, they added.

The current evidence on bisphosphonate use
and atypical fractures is conflicting. A recent meta-analysis of randomized
trials found no association. But a registry-based study suggested that the risk
of atypical fracture was more than doubled when bisphosphonates were taken for longer
than 5 years.

In 2010, the FDA confirmed that
bisphosphonate drugs for osteoporosis carried a small but meaningful risk of femoral fractures
and ordered an update to product labels.

To add to the data on the subject, Meier's
group identified patients admitted to their level I trauma center with a
fracture of the subtrochanteric femoral shaft area between 1999 and 2010 and
divided them into two groups.

One arm consisted of patients with
atypical fractures, defined as "a transverse or short oblique fracture
line originating at the lateral femoral cortex between the lesser trochanter
and the distal metaphysis."

Another arm was made up of patients with
common or classic fractures that were in the same location as atypical
fractures, but with spiral, wedge, segmental, or complex irregular appearance.

They also established a control group of
people who did not have a history of femoral fracture.

In addition to more atypical fractures
among the group taking bisphosphonates, 28.2 percent of the atypical group had
a contralateral fracture compared with 0.9 percent in the classic-fracture
group.

In the atypical group, all of the complete
and incomplete fractures were in patients taking bisphosphonates.

Recurrent fracture was also more common in
the atypical-fracture group compared with the classic-fracture group.

After adjustment for potential risk
factors, including vitamin D status, corticosteroids, proton pump inhibitor
use, sex, and age, the authors found that any bisphosphonate use was associated
with an OR of 69.1 for an atypical fracture versus a classic fracture.

When categorized by duration of treatment
compared with no treatment, the OR for an atypical fracture compared with a
classic fracture was:

OR 35.1 for less than 2 years of treatment

OR 46.9 for 2 to 5 years

OR 117.1 for 5 to 9 years

OR 175.7 for more than 9 years

When comparing the atypical-fracture group
with the control group, the authors reported that bisphosphonate treatment was
associated with an OR of 35.2.

Despite these results, the authors pointed
out that "averaged over the 12 years of observation ... the incidence rate
[for atypical fracture] is very low; there were 11 times more classic fractures
during the same period," adding that bisphosphonate therapy still comes
out ahead for reducing vertebral fractures by as much as 70 percent and wrist
fractures by 50 percent.

And they cautioned that their
retrospective design does not allow for definitive conclusions on causality.

But the study "adds further data
suggesting that the association between bisphosphonate use and atypical
fractures is causal," said Douglas Bauer, MD, of the University of
California San Francisco, in an accompanying commentary.

"These and other high-quality studies
lead to the following conclusions: bisphosphonate therapy can prevent spine and
nonspine fractures among appropriately selected high-risk individuals ... and
atypical subtrochanteric and femoral shaft fractures may be more frequent after
bisphosphonate therapy but are rare compared with typical osteoporotic
fractures," wrote Bauer.

The current data also draw attention to
the idea that the antifracture efficacy of bisphosphonates may not last beyond
a certain number of years. Bauer suggested that some older women could consider
stopping therapy after 3 to 5 years, which may mean less atypical fractures but
at the cost of additional vertebral fractures.

Meier's group, which acknowledged that
they lacked sufficient information on confounding factors such as bone density, use of other medications, body mass index, smoking
history, and exercise history, called for more research to determine why so few
patients taking bisphosphonates have atypical fractures, and why these
fractures also occur in people without any history of bisphosphonate use.

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